Abstract Palpation has been used for hundreds of years in medicine to differentiate various types of tissues and masses within tissue. In technical terms, palpation can be defined as deformation of tissue in response to a force, which in linear mechanics is defined as tissue elasticity. The concept of tissue elasticity i.e. elastography has been the subject of intense investigations in the past two decades. However, recent studies have shown that tissue behaves nonlinearly at larger strains, whereby the nonlinear elasticity of tissue may carry important diagnostic information. The long-term objective of this research is the development of a novel diagnostic technique that (i) makes use of the acoustic radiation force (ARF) for noninvasive tissue interrogation, and (ii) deploys a novel coefficient of nonlinear tissue elasticity as a biomarker that is sensitive to tissue type. One possible application of the method, initiated in this study, is the differentiation of breast masses; however, the proposed method may find applications in other organs. The proposed study is made possible by the recent discovery by our research team that the magnitude of the ARF in soft tissues depends linearly on a particular coefficient of nonlinear tissue elasticity, hereon denoted by C ? that quantifies the gain in shear wave speed due to increasing hydrostatic pressure. The basic idea behind the method is to act upon tissue by the ARF at a point of interest (e.g. inside a breast mass) and to monitor the ARF-generated generated shear waves via ultrasound. In this setting, the nonlinear modulus C can be computed from the amplitude of the observed shear waves ? a claim that is supported by our preliminary data on tissue-mimicking phantoms and animal tissues. The proposed approach to nonlinear tissue elastography is novel in that: (a) it focuses on the volumetric-shear modulus C that has eluded previous studies, and (b) it enables, for the first time, local evaluation of nonlinear tissue elasticity with a spatial resolution given by the size of the focal region (order of mm). This makes it possible to locally measure C over the volume of the focal region using the ARF. For this reason, the proposed method is hereon referred to as nonlinear C-Elastography (CE). To assess the effectiveness of CE, we first propose to create well-characterized phantoms with (tissue-mimicking) lesions and create their C-images to be compared with the respective linear (e.g. shear modulus) elastograms. The last stage of our study would focus on the ex-vivo testing of breast masses, through which we will be able to correlate the CE results to tissue pathology and assess the overall effectiveness of CE. Successful completion of this research will spur the development of a noninvasive, diagnostic tool that may have significant impact in early differentiation of breast masses and potentially pathologies in other organs.